chr19-5679748-TC-T

Position:

• chr19-5679748-TC-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_205767.3(MICOS13):​c.44del​(p.Gly15GlufsTer75) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MICOS13 NM_205767.3 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity no assertion criteria provided P:1 U:1
• Conservation: PhyloP100: 2.67

Genes affected

MICOS13 (HGNC:33702): (mitochondrial contact site and cristae organizing system subunit 13) Involved in cristae formation. Located in mitochondrial crista junction and nucleoplasm. Part of MICOS complex. Implicated in combined oxidative phosphorylation deficiency 37. [provided by Alliance of Genome Resources, Apr 2022]

RPL36 (HGNC:13631): (ribosomal protein L36) Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of 4 RNA species and approximately 80 structurally distinct proteins. This gene encodes a ribosomal protein that is a component of the 60S subunit. The protein belongs to the L36E family of ribosomal proteins. It is located in the cytoplasm. Transcript variants derived from alternative splicing exist; they encode the same protein. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.877 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MICOS13	NM_205767.3	c.44del	p.Gly15GlufsTer75	frameshift_variant	2/4	ENST00000309324.9
MICOS13	NM_001308240.2	c.110del	p.Gly37GlufsTer75	frameshift_variant	3/5
MICOS13	NM_001365761.2	c.110del	p.Gly37GlufsTer75	frameshift_variant	2/4
MICOS13	XM_011527675.3	c.110del	p.Gly37GlufsTer95	frameshift_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MICOS13	ENST00000309324.9	c.44del	p.Gly15GlufsTer75	frameshift_variant	2/4	1	NM_205767.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Combined oxidative phosphorylation deficiency 37 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 22, 2019

- -

Mitochondrial hepato-encephalopathy Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

The Raphael Recanati Genetics Institute, Rabin Medical Center

Sep 13, 2018

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1568293814; hg19: chr19-5679759;